Please use this identifier to cite or link to this item:
https://doi.org/10.1186/s13195-015-0137-y
Title: | Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans | Authors: | Ling, I.-F Golde, T.E Galasko, D.R Koo, E.H |
Keywords: | amyloid beta protein amyloid precursor protein gamma secretase gamma secretase inhibitor ibuprofen indometacin nonsteroid antiinflammatory agent placebo sulindac sulfide amyloid beta protein amyloid beta protein[1-40] amyloid beta-protein (1-42) amyloid precursor protein APP protein, human ibuprofen nonsteroid antiinflammatory agent peptide fragment secretase Alzheimer disease animal experiment Article cerebrospinal fluid CHO cell line controlled study degenerative disease drug blood level electrospray female gene mutation human in vitro study in vivo study Macaca fascicularis neuromodulation nonhuman nuclear magnetic resonance primate priority journal protein cleavage risk reduction single drug dose thin layer chromatography adult animal blood Cricetulus dose response genetics male metabolism randomization time factor treatment outcome young adult Adult Amyloid beta-Peptides Amyloid beta-Protein Precursor Amyloid Precursor Protein Secretases Animals Anti-Inflammatory Agents, Non-Steroidal CHO Cells Cricetulus Dose-Response Relationship, Drug Female Humans Ibuprofen Macaca fascicularis Male Peptide Fragments Random Allocation Time Factors Treatment Outcome Young Adult |
Issue Date: | 2015 | Citation: | Ling, I.-F, Golde, T.E, Galasko, D.R, Koo, E.H (2015). Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans. Alzheimer's Research and Therapy 7 (1) : 55. ScholarBank@NUS Repository. https://doi.org/10.1186/s13195-015-0137-y | Rights: | Attribution 4.0 International | Abstract: | Introduction: Ibuprofen is one of the nonsteroidal anti-inflammatory drugs that have been shown to selectively lower pathogenic amyloid beta-peptide (Aβ)42 without impairing overall γ-secretase activity in vitro. This γ-secretase modulator (GSM) activity has been hypothesized to contribute to the reduction in risk of developing Alzheimer's disease in chronic users of nonsteroidal anti-inflammatory drugs. However, it is unclear whether ibuprofen, within therapeutic dosing range, demonstrates GSM activity in humans. In this study, we evaluated the effects of ibuprofen and a second-generation GSM, GSM-1, on Aβ levels in cerebrospinal fluid and plasma of young nonhuman primates and humans. Methods: Five to seven conscious cynomolgus monkeys (Macaca fascicularis) were nontreated or treated with 30 mg/kg GSM-1 or 50 or 100 mg/kg ibuprofen and the plasma and cerebrospinal fluid were sampled at -8, 0 (baseline or right before treatment), 2, 4, 6, 8, 12, and 24 h postdosing. In addition, sixteen healthy human subjects were randomly assigned to receive either placebo or 800 mg ibuprofen given by intravenous administration and plasma were collected at 0 (before drug infusion), 0.5, 1, 2, 4, 6, 8, 10, and 24 h after dosing. Results: A single dose of GSM-1 (30 mg/kg) decreased the ratio of Aβ42 to Aβ40 to 60 % in plasma and the ratio of Aβ42 to total Aβ to 65 % in cerebrospinal fluid from baseline to postdosing in monkeys. However, no significant changes were detected following ibuprofen treatment at 100 mg/kg. Consistent with the results from nonhuman primates, ibuprofen did not alter plasma Aβ levels in human volunteers after a single 800 mg dose. Conclusions: GSM-1 exerted potent lowering of the ratio of Aβ42 to Aβ40 in nonhuman primates but the hypothesized GSM activity of ibuprofen could not be demonstrated in nonhuman primates and humans after acute dosing. © 2015 Ling et al. | Source Title: | Alzheimer's Research and Therapy | URI: | https://scholarbank.nus.edu.sg/handle/10635/180902 | ISSN: | 17589193 | DOI: | 10.1186/s13195-015-0137-y | Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
Show full item record
Files in This Item:
File | Description | Size | Format | Access Settings | Version | |
---|---|---|---|---|---|---|
10_1186_s13195-015-0137-y.pdf | 1.26 MB | Adobe PDF | OPEN | None | View/Download |
This item is licensed under a Creative Commons License